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Sara Pichelli began her career in animation, working as a storyboard artist, animator and character designer. She said of this work, "It wasn't really for me. I felt like a tiny cog in a machine."[1] She started working in the comic book industry after meeting comics artist David Messina. Prior to that, she was not particularly interested in comics and preferred animated films and anime.[1] She worked as a layout assistant for Messina and worked on such titles as the Star Trek comic book series produced by IDW Publishing, including such editions as Star Trek: Countdown and Star Trek: Nero.[2] In 2008 she submitted her work to the Chesterquest international talent search and was named one of the finalists by Marvel Comics editor C. B. Cebulski, which led to her working for Marvel. She illustrates for Marvel from her home in Rome.[1]

Pichelli uses a Cintiq 12wx graphic tablet. When illustrating Ultimate Comics: Spider-Man,[8] she added more screentones to her illustrations to give what she called "a more 'pop' feeling to the book", as she believed it would be more fitting to that series.[10]

In creating the visual look of characters, Pichelli approaches the design by giving thought to the character's personalities, including the background that may have influenced them, and the distinctive traits that the characters exhibit, such as the clothing they wear, their body language and expressions. She followed this approach when creating Miles Morales.[11]

There are three or four artists we've got at Marvel who are really starting to pop and sizzle and define a new look and style that's distinctly their own. We look at these people as being the next generation of Marvel superstars, and I think Sara is clearly one of them. Her stuff is bubbly and fun and alive and energetic and exciting. It has all the best traits and qualities of humanity and engagingness [that] I'd want in a Marvel artist.

Pichelli won a 2011 Eagle Award for Favorite Newcomer Artist,[12] beating out fellow nominees Rafael Albuquerque, Fiona Staples, Sean Murphy and Bryan Lee O'Malley.[13] Marvel Comics senior editor Mark Paniccia said of Pichelli: "Every time I see new pages from Sara she continues to grow as an artist. She's amazing now and I can't imagine where she'll be a year from now."[4] Marvel Comics editor Tom Brevoort called her "a real breakout talent" and "a top talent primed to explode in a major way".[1] David Brothers of ComicsAlliance praised her attention to detail and said he particularly likes the way Pichelli draws hair, facial expressions and body language: "The first two add a lot to the atmosphere of the comics she draws, and the third cranks her storytelling up to another level."[3]IGN writer Jesse Schedeen called Pichelli's art in Ultimate Fallout "energetic, cinematic, and just flamboyant enough to offer a change of pace from the rest of the Ultimate Fallout stories".[14]